The circadian clock regulates physiology and behavior and impinges on many aspects of our daily life. Nowhere is this more obvious than control of the sleep wake cycle, where clock genes have been shown to play a role in both the timing of sleep and its quality. For example, mutations in PER2 cause familial advanced sleep phase syndrome (FASPS), while mutations in CSNK1E and CSNK1D cause FASPS and delayed sleep phase syndrome (DSPS), respectively. However, while we have learned much about the clock and how it regulates sleep, the picture is incomplete. Behavioral studies in mice and studies in human cells show that dozens to hundreds of loci impact circadian clock function. However, only a dozen genes have been investigated for their roles in regulating behavior. Testing dozens to hundreds of mice isn't practical, so a new approach is needed. Here we seek to address this gap with a novel strategy that uses, i) integrative bioinformatics to prioritize putative core clock factors, ii) new experimental methods to determine whether they interact with known clock genes and regulate clock function in several cellular or tissue slice models, and, finally, iii) for a subset of promising candidates, generate mouse models and test them for their roles in regulating circadian behavior and sleep. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans. PUBLIC HEALTH RELEVANCE: Our internal biological clocks control many important aspects of our physiology and behavior such as the sleep-wake cycle. Genetics and large-scale genomic studies have implicated the role of a dozen canonical and hundreds of additional new genes in the circadian clock. However, almost none of the new genes have been studied in animal models for their ability to regulate sleep onset or quality. We will address this gap using bioinformatics, experimental biology, and finally through behavioral analysis. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans.